Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography

• DOI: 10.7554/elife.81167
• Publication Date: 2022-11-22T00:00:15Z
• Authors: Alberto Borsatto; Obaeda Akkad; Ioannis Galdadas; Shumeng Ma; Shymaa Damfo; Shozeb Haider; Frank Kozielski; Carolina Estarellas; Francesco Luigi G...
• Keywords: Druggability; Coronavirus; 2019-20 coronavirus outbreak; Sars virus

Non-structural protein 1 (Nsp1) is a main pathogenicity factor of α- and β-coronaviruses. Nsp1 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppresses the host gene expression by sterically blocking 40S ribosomal subunits promoting mRNA degradation. This mechanism leads to downregulation translation-mediated innate immune response in cells, ultimately mediating observed evasion capabilities SARS-CoV-2. Here, combining extensive molecular dynamics simulations, fragment screening crystallography, we reveal druggable pockets Nsp1. Structural computational solvent mapping analyses indicate partial crypticity these newly discovered binding sites. The results fragment-based via X-ray crystallography confirm druggability major pocket Finally, show how targeting this could disrupt Nsp1-mRNA complex open novel avenue design new inhibitors for other Nsp1s present homologous